The following case study focuses on a 55-year-old male with
multiple myeloma and prognosis of undetermined significance. Test your
knowledge by reading the background information below and making the proper
A 55-year-old male presents to your office with new symptoms
of exertional fatigue. He is otherwise well with no significant past medical
history. His hemoglobin is found to be low at 10.6g/dl, with an MCV of 92. He
has normal serum ferritin, vitamin B12, and folic acid levels. Absolute
neutrophil count is 1.3 x 103/ul and platelets 117 x 109/uL.
He has a creatinine of 0.9 mg/dL, calcium of 9.2 mg/dL, and albumin of 3.8
g/dL. A serum protein electrophoresis is performed that demonstrates a
monoclonal IgA protein of 1.5 g/dL. A skeletal survey shows occult lytic
lesions in the skull and bilateral humeri, and a bone marrow biopsy shows 30
percent involvement by abnormal appearing plasma cells, confirmed by CD138+
You make a diagnosis of symptomatic multiple myeloma and
review the findings and need for treatment with the patient. The patient wishes
to know more about his prognosis and chances of responding to therapy. You
explain that you are awaiting a few additional test results that will help you
answer his question. Which result would not
be considered a poor prognostic feature in this patient with newly diagnosed
microglobulin of 7mg/L
13 abnormality by standard karyotype
Initial diagnostic work-up for
patients with multiple myeloma (MM) should include both conventional
karyotyping as well as fluorescence in
situ hybridization (FISH) of plasma cells obtained from bone marrow
aspiration. FISH should be assessed for poor-risk translocations, including
t(4;14) (MMSET translocation; 75 percent of which express FGFR3), t(14;16) (MAF
translocation), and deletion 17p (loss of p53). The presence of a chromosome 13
abnormality (monoallelic loss of chromosome 13 or deletion of its long arm 13q)
by standard karyotype also confers a poor prognosis. However, when a chromosome
13 abnormality is detected only by FISH the significance is less clear and does
not seem to confer the same poor prognosis. It has been suggested that
detection of del
13 on karyotype analysis is a surrogate for the proliferative rate of the tumor
clone. The t(11;14) translocation, which juxtaposes the cyclin D1 gene with the
IgH promoter, is associated with a neutral to favorable prognosis in multiple
myeloma. Additionally, a hyperdiploid karyotype also carries a more favorable
prognosis in multiple myeloma and is a distinct biologic entity from
The International Staging System
(ISS) for multiple myeloma uses β-2 microglobulin and serum albumin to divide
patients into stage I, II, or III disease. A β-2 microglobulin level ≥ 5.5 mg/L
would classify a patient as stage III disease, with a median survival of 29
months with conventional chemotherapy (about 80 percent of studied patients) or
upfront high-dose chemotherapy and autologous stem cell transplantation (about
20 percent of studied patients). This is compared to a median survival of 62
months for those with stage I disease (β-2 microglobulin < 3.5 mg/L and
serum albumin ≥ 3.5 g/dL).5 Therefore, the ISS remains a powerful
and simple non-genetic model to stratify MM patients. However, it should be
noted that the ISS prognostic model will need to be validated in the era of
novel agents, since drugs such as bortezomib and lenalidomide may overcome the
negative predictors in this model.
Currently, there is not a standard
recommendation to treat poor-risk patients differently from standard-risk
patients, however this is the subject of ongoing clinical studies. It is
important to note though that bortezomib appears to ameliorate or eliminate the
prognostic significance of these historically poor-risk features (particularly
deletion 13, and translocation 4;14) and is generally recommended as part of
the induction strategy in such patients. The ability of immunomodulatory drugs
such as lenalidomide to overcome poor-risk features has not been as clearly
shown to date.6-8
Note: The true teaching point of
this case study is that t(11;14) exists in mantle cell lymphoma and multiple
myeloma, and it may identify a possibly good prognostic group.
- Fonseca R, Barlogie B, Bataille R, et
and cytogenetics of multiple myeloma: a workshop report. Cancer Res.
- Avet-Loiseau H, Attal M, Moreau P, et
abnormalities and survival in multiple myeloma: the experience of the
Intergroupe Francophone du Myélome. Blood. 2007;109:3489-3495.
- Chng WJ, Santana-Dávila R, Van Wier
SA, et al. Prognostic
factors for hyperdiploid-myeloma: effects of chromosome 13 deletions and
IgH translocations. Leukemia. 2006;20:807-813.
R, Bergsagel PL, Drach J, et al. International Myeloma
Working Group molecular classification of multiple myeloma: spotlight review.
PR, San Miguel J, Durie BG, et al. International staging
system for multiple myeloma. J Clin Oncol. 2005;23:3412-3420.
S, Richardson PG, Sonneveld P, et al. Bortezomib appears to
overcome the poor prognosis conferred by chromosome 13 deletion in phase 2
and 3 trials. Leukemia. 2007;21:151-157.
Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan
and prednisone for initial treatment of multiple myeloma. N Engl J
- Kumar SK, Mikhael JR, Buadi FK, et al. Management of newly
diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma
and Risk-Adapted Therapy (mSMART) consensus guidelines. Mayo Clin Proc. 2009;84:1095-1110.
Case study submitted by Nicholas Burwick, MD, Hematology/Oncology Fellow, University of Washington, Fred Hutchinson Cancer Research Center.
back to top